Antihyperlipidemic/antioxidant dihydroquinolines

ABSTRACT

The present invention relates to novel dihydroquinolines which are useful for cholesterol lowering and as antioxidant agents. Also provided is a process for preparing the dihydroquinolines of the present invention, pharmaceutical compositions, and a method of treating or inhibiting hypercholesterolemia, hyperlipidemia, atherosclerosis, and LDL oxidation which comprises administering to birds and mammals in need of such treatment an effective amount of a compound of the present invention.

This is a divisional of application Ser. No. 08/048,696 filed Apr. 16,1993 now U.S. Pat. No. 5,411,969.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention provides novel dihydroquinolines which areeffective as LDL lowering agents and which also have antioxidantcapacity.

2. Description of Related Art

It is generally recognized that high blood cholesterol levels aresignificant risk factors in cardiovascular disease.

It has been established that 3-hydroxy-3methylglutaryl coenzyme Areductase (HMGR) is the first rate limiting enzyme in the biosyntheticpathway for cholesterol, that inhibition of HMGR activity results in adecrease in serum total cholesterol and low density lipoprotein (LDL)cholesterol levels, and that a decrease in serum LDL-cholesterol levelsis reflected in a reduction of plasma level of apolipoprotein B. (Brown,et al, J. Lipid Res, 21: 505-517 (1980)).

Tocotrienols have been shown to suppress HMGR resulting in theinhibition of cholesterol biosynthesis and a subsequent drop in LDLcholesterol, apolipoprotein B, thromboxane B₂, platelet factor 4 andglucose levels. (Wright, et al, A Symposium On Drugs Affecting LipidMetabolism, Houston, Tex. (Nov. 1989)).

The tocotrienols are structurally related to the tocopherols (vitamin E)and differ only by possessing unsaturation in the isoprenoid side chain.Like the tocopherols, the tocotrienols have antioxidative activity.(Yamaoka, et al, Yukagaku, 34: 120-122 (1985); Serbinova, et al, FreeRadical Biology and Medicine, 10: 263-275 (1991)).

Active oxygen species are known to play pivotal roles in the genesis ofatherosclerotic plaques, thrombotic episodes, ischemic damage, cancer,aging, dementia, and inflammatory conditions. (Sies, H., OxidativeStress; Academic Press, New York, (1985); Santrucek, M., Krepelka, J.,Drugs of the Future, 13: 73-996 (1988); Steinberg, Circulation, 84:1400-24 (1991)). Of particular interests are the potential protectiveeffects of antioxidants on lipoproteins, since oxidized LDL is thoughtto be atherogenic. (Buckley et. al., Drugs, 37: 761-800 (1989); Gwynneet. al., Am. J. Cardiology, 62: 1B-77B (1988)).

PROBUCOL(4,4'-[(1-methylethylidene)bis(thio)]-bis[2,6-bis(1,1-dimethylethyl)](Lorelco, Marion Merrell Dow)(Formula I) is a hypolipidemic drug, whichis also an excellent antioxidant. PROBUCOL inhibits the oxidativemodification of LDL both in vitro and in vivo. (Steinberg, Am. J.Cardiol., 57: 16H-21H (1986)). PROBUCOL, however, suffers frombioavailability problems, exhibits only modest reductions in LDLcholesterol, and has undesirable effects on HDL cholesterol. ##STR1##

Esterbauer et al. (Dieber-Rotheneder, et al., J. Lipid Res., 32: 1325-32(1991)) have examined the oxidative resistance of LDL as a function oforal vitamin E supplementation. While the oxidative resistance of LDLwas significantly enhanced during vitamin E supplementation, antioxidanteffectiveness varied considerably from subject to subject.

6-Ethoxy-2,2,4-trimethyl-3,4-dihydroquinoline (ETHOXYQUIN, Tokyo Kasai)is widely used as a feed preservative marketed under the name ofSANTOQUIN [Formula II]. This antioxidant chemotype has been incorporatedinto retinoic acid derivatives, and were evaluated as acancer-prevention agents. (Welch, et al., J. Med. Chem., 25: 81-84(1982)). The water soluble analogue MTDQ-DA [Formula III] has beeninvestigated as a antiatherosclerotic drug in cholesterol fed rabbits.(Pollak-Bar, et al., Fat Science Proc., 16th ISF Congress, 1059-1067(1983)). MTDQ-DA mediated fairly modest effects on various lipidparameters, however this compound completely inhibited plaqueprogression relative to the cholesterol fed rabbit controls. ##STR2##

While the causative factors in the development of atherosclerosis aremany, two important ones are elevated serum cholesterol levels andexcessive LDL oxidation.

The above compounds do not successfully unite lipid lowering andantioxidant potential. The present describes the successful union ofthese two pharmacological properties in dihydroquinolines.

SUMMARY OF THE INVENTION

The present invention provides novel dihydroquinolines which combinelipid lowering with antioxidant effectiveness.

An aspect of the present invention provides dihydroquinolines which areuseful for cholesterol/lipid lowering in cases of hypercholesterolemia,hyperlipidemia, atherosclerosis and which are also useful to inhibit LDLoxidation.

Another aspect of the present invention provides a pharmaceuticalcomposition which comprises at least one compound of the presentinvention and a non-toxic pharmaceutically acceptable carrier.

Another aspect the present invention provides a method of treatinghypercholesteremia, hyperlipidemia and thromboembolic disorders in birdsand mammals, including humans which consists of administering at leastone compound of the present invention to a host in need of suchtreatment.

Another aspect of the present invention provides a method of inhibitingcholesterol biosynthesis, lowering LDL cholesterol, and inhibiting LDLoxidation in birds and mammals, including humans which consists ofadministering at least one compound of the present invention to a hostin need of such treatment.

Another aspect of the present invention provides intermediates usefulfor making the dihydroquinolines of the present invention.

These and other advantages and objects of the invention will be apparentto those skilled in the art.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides compounds of the general Formula IV##STR3## wherein X is O, S or CH₂

R¹ is H or ##STR4## R² and R³ are independently H, C₁ -C₅ alkyl, CF₃,CN, halogen or OCH₃,

n is an integer of 0 to 3, and

m is an integer of 1 to 3,

or a pharmaceutically acceptable salt thereof.

As used herein and in the claims, the term "C₁ -C₅ alkyl" is meant toinclude saturated or unsaturated, branched or straight chain alkylgroups of one to five carbon atoms, including but not limited to methyl,ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, and the like. Theterm "halogen" is meant to include fluorine, chlorine, bromine, andiodine.

Also included within the scope of the present invention arepharmaceutically acceptable acid addition salts, the metal salts, andthe solvates of the compounds of Formula IV, which may exist in varioustautomeric forms.

The synthesis of the farnesylated dihydroquinoline (4) is shown inscheme I. ETHOXYQUIN (Tokyo, Kasai) (1) was dealkylated with hothydrobromic acid to give the known crystalline phenol (2). This materialwas bis-acetylated to give the amide-ester intermediate. Selectivedeprotection with methanolic KOH gave the amide 3. The side chain couldbe attached by either coupling through a Mitsunobu-type procedure or bydirect alkylation. The Mitsunobu procedure was somewhat capricious, andin general the alkylation proved the better method of synthesis. Removalof the amide protecting group was smooth using excess lithiumtriethylborohydrate. Use of the amide protecting group was notabsolutely necessary, however the yields were significantly better inits presence. ##STR5##

The sulfide 8 was prepared as shown in scheme II. The S-aryldimethylthiocarbamate 6 was obtained by a Newman-type rearrangement(Newman, et al., J. Org. Chem., 31: 3980-84 (1966)) of O-aryldimethylthiocarbamate 5. The reaction goes in good yield when catalyzedwith p-toluenesulfonic acid under strictly oxygen-free conditions.N-Protection is absolutely necessary in this case as the correspondinganiline-thiol is very unstable. The dimethylthiocarbamate 6 is unmaskedwith sodium methoxide in methanol to give thiol 7. The alkylation anddeprotection were done as described in scheme I. ##STR6##

Synthesis of the methylene-linked analogue of compound 4 can beaccomplished via the sequence shown in scheme III. The dihydroquinolineis obtained from the iodine catalyzed reaction of aniline 9 and acetonefollowing a general procedure. (Org. Syn. Coll., 3: 329). Thefarnesylethyl side chain is attached by alkylation to the sulfonemoiety. The nitrogen must be protected during this step to avoiddecomposition under basic conditions. The reductive cleavage of thesulfone and super-hydride removal of the amide were smooth, and yieldedcompound 11 as indicated in scheme III. ##STR7##

The route to1,2-dihydro-2,2,4-trimethyl-6-[[5-methyl-7-[3-(trifluoromethyl)phenyl]-4(E)hexenyl]oxy]quinoline(18) is shown in scheme IV, and follows a similar strategy as depictedin scheme III. Starting with 5-methyl-4-hexenal, (Marbet, et al., Helv.Chim. Acta, 50: 2095-3000 (1967)) reduction, alcohol protection, andozonolysis proceeded smoothly to give the 4-silyloxybutanal 12. TheHorner-Emmons olefination of 12 gave a 10:1 mixture of E:Z isomers,which could be chromatographically separated. The purified E-enoate 13was reduced in a 1,2-fashion with dibal-H to give the allylic alcohol14. The alcohol was converted into the chloride 15 and coupled with thelithium salt of sulfone 10. The toluenesulfonyl activating group wasremoved with sodium amalgam in buffered methanol and the crude materialwas then treated with fluoride to give the alcohol. The alcohol wasconverted into the primary iodide 17 by a standard Finklesteinprocedure. Coupling of iodide 17 to the N-acetyl dihydroquinoline 3under basic catalysis followed by amide removal proceeds smoothly togive the final target compound 18. ##STR8## HepG2 Cell Culture Moldel

The human hepatoma HepG2 cell culture model was employed to compare theintrinsic activities of the representative compounds of the presentinvention relative to the tocotrienols. HepG2 cells were incubated withthe indicated compounds for 4 hours at 10 μM. Cholesterol synthesis wasassayed by ¹⁶ C-acetate incorporation over the final hour of incubation,and HMG-CoA reductase suppression (specific activity) was assayed in themicrosomal fraction isolated from parallel cultures at the end of the 4hour incubation. Time course studies (not shown) indicated that 4 hourspreincubations provided maximal suppression of sterol synthesis. Theresults are shown in Table I.

                  Table I                                                         ______________________________________                                                     Percent of Control                                               Compound       Cholesterol                                                                              HMGR                                                10 μm       Biosynthesis                                                                             Suppression                                         ______________________________________                                        γ-Tocotrienol                                                                          29         65                                                   4             48         40                                                   8             3          N.T.                                                11             89         N.T.                                                18             42         N.T.                                                ______________________________________                                         N.T. = Not Tested                                                        

In Vivo Evaluation of Synthetic Analogues in NormocholesterolemicChickens

Hypocholesterolemic activity was evaluated for representative compoundsof the present invention using γ-tocotrienol as a control innormocholesterolemic chickens. Newborn male chicks (6-10 for each group)were raised on a standard corn-soybean-based control diet for two weeksand then were switched to either control or experimental diets for fourweeks. Drug treatment consisted of the addition of test compound to thecorn-soybean-based. At the end of the feeding period, all the birds werefasted (about 36 hours) and refed (about 48 hours) to inducecholesterolgenic enzymes prior to sacrifice. The specific activity ofHMG-CoA reductase, total serum cholesterol levels, and HDL/LDLcholesterol pools were examined (Table II).

                  Table II                                                        ______________________________________                                        Effects of Compounds of the present invention on Lipid                        Parameters in Male Chickens                                                   Orally dosed for 4-weeks at 4 mg/kg/day                                               Values Given as % of Control                                          Compound  Tot.-C  LDL-C      HDL-C  HMGR                                      ______________________________________                                        γ-Tocotrienol                                                                     76.3    54.8       87.0   N.T.                                      4         65.9    45.3       89.0   83.8                                      8         100.9   99.1       98.2   N.T.                                      18        61.2    26.0       93.8   66.4                                      ______________________________________                                         N.T. = Not Tested                                                        

Antioxidant Evaluation

There are a number of ways in which one can evaluate a biologicalantioxidant. (Halliwell, Free Rad. Res. Comms., 9: 1-32 (1990)). Theability of test compounds to inhibit the oxidative modification of LDLis what is most relevant here. (Bedwell, et al., Biochem. J., 262:707-12 (1989)). The oxidative modification of LDL has been examined invitro, using both copper and cellular (enzymatic) mediated processes.Esterbauer et al. have developed a conjugated diene assay for themeasurement of LDL Oxidation. (Esterbauer, et al., Free Rad. REs.Comms., 6: 67-75 (1989)). The oxidation of polyunsaturated lipids causesthe conjugation of double bonds that can be quantitatively measuredspectrophotometrically. The conjugated diene assay appears to besuperior to older methods such as the measurement of thiobarbituric acidreactive substances (TBARS). (Yagi, Chem. Phys. Lipids, 45: 337-351(1987)).

One method for the measurement of general antioxidant capacity isstopped-flow kinetic analysis. (Mukai, et al., Bull. Chem. Soc. Jpn.,59: 3113-3116 (1986); Mukai, et al., J. Org. Chem., 54: 557-560 (1989);Mukai, et al. J. Org. Chem., 53: 430-432 (1988)). This is asophisticated setup wherein, one measures radical transfer from a stableradical, (for example 2,6-di-tert-butyl-4-(4-methoxyphenyl)phenoxy), toa test compound spectrophotometrically as a function of time. Mukai etal. have demonstrated that a linear relationship exists betweensecond-order rate constants derived from stopped-flow measurements andtheir half-peak oxidation potentials as measured voltammetrically.(Mukai, et al., Bull. Chem. Soc. Jpn., 59: 3113-3116 (1986); Mukai, etal., J. Org. Chem., 54: 557-560 (1989); Mukai, et al. J. Org. Chem., 53:430-432 (1988)). Voltammetry has been used by Moldeus et al. to studythe antioxidant capacity of structurally relateddibenzo[1,4]dichalcogenines as inhibitors of lipid peroxidation.(Cotgreave, et al., Biochem. Pharm., 42: 1481-85 (1991)). In their case,a strong correlation between voltammetric potential and the ability toinhibit lipid peroxidation was observed.

As a secondary screen, test compounds are evaluated ex vivo for theiroral effectiveness to inhibit LDL oxidation. In this assay, a betterassessment of drug biodistribution into LDL particles is obtained.Again, the conjugated diene assay is used to assess lipid peroxidation.

Redox Potential and In Vitro LDL Oxidation

The general antioxidant capacity of several reference agents and thecompounds of the present invention as measured by cyclic voltammetry isshown in Table III. A linear dependence of oxidation potentials tohydrogen atom donation capacity exists for compounds of similarstructure. (Mukai, et al., J. Org. Chem., 53: 430-432 (1988); Mukai, etal., J. Org. Chem., 55: 552-556 (1989); Mukai, et al., J. Org. Chem.,56: 4188-4192(1991)). The lower the oxidation potential (voltage) theeasier the compound is to oxidize. For the in vitro LDL oxidation assay,(Steinbrecher, et al., Proc. Natl. Acad. Sci. U.S.A., 81: 3883-3887(1984)) test compounds were incubated (10 μM) with fresh plasma derivedfrom rabbits maintained on a diet which enriches LDL in linoleatecontent; LDL was then isolated from the treated plasma, dialyzed, andincubated under oxidizing conditions (added Cu⁺⁺). Oxidation wasmeasured spectrophotometrically by conjugated diene formation and thelag time extension versus control (ratio of treated/control) wasdetermined from the first derivative of the A₂₃₄ kinetic curves.

                  TABLE III                                                       ______________________________________                                        Redox Potential and In Vitro LDL Oxidation                                                Oxd. Potential     LDL Oxd. Inhib.                                Compound    Volts        n     mean lag ratio                                 ______________________________________                                        Butylatedhydroxy-                                                                         N.T.         1     1.38                                           toluene                                                                       PROBUCOL    1.12         28    1.38                                           ETHOXYQUIN  N.T.         1     1.21                                           Ascorbate   N.T.         1     1.00                                           α-Tocopherol                                                                        0.81         5     1.01                                           γ-Tocopherol                                                                        N.T.         2     1.17                                           γ-Tocotrienol                                                                       0.94         3     1.27                                           4           0.47         6     1.80                                           8           1.20         1     1.64                                           ______________________________________                                         N.T. = Not Tested                                                        

Ex Vivo LDL Antioxidant Effects of Standard Reference Agents andCompounds of the Present Invention

Hamsters (n=6 per group) were placed on an atherogenic diet (0.4%cholesterol+10% vitamin E stripped corn oil), and were orally dosed for17 days with the indicated compounds at 75 mpk/day. The resistance ofhamster LDL to copper-dependent oxidation in vitro was determined byconjugated dienes or lipid peroxides. (Esterbauer, et al., Free Rad.Res. Comms., 6: 67-75 (1989)). Table IV gives the lag phase extensionvalues (lag ratio) estimated from the conjugated diene curves, and therate of initial formation of lipid hydroperoxides during LDL oxidationby Cu⁺⁺ in vitro (given as % of control at the early incubation timepoints).

                  TABLE IV                                                        ______________________________________                                        Ex Vivo LDL Lipid Peroxidation Assay                                                                   % of     % of                                        Compound    Conj. Dienes Control  Control                                     (mg/kg/d)   lag ratio (a)                                                                              1.5 h (b)                                                                              3.0 h (b)                                   ______________________________________                                        Probucol (50)                                                                             1.12         48       93                                          α-Tocopherol                                                                        >3           15       36                                          (50)                                                                          γ-Tocotrienol                                                                       1.48         7        67                                          (50)                                                                          Na Ascorbate                                                                              1.33         8        91                                          (50)                                                                          4(50)       1.57         3        31                                          Ethoxyquin (75)                                                                           1.81         0        13                                          ______________________________________                                         (a) Measures the ability of the antioxidant to inhibit initiation of          conjugated diene formation in LDL as a function of time, expressed as         treated/control.                                                              (b) Measures the ability of the antioxidant to inhibit lipid peroxide         formation in LDL at 1.5 hour and 3 hour time points.                     

The antioxidant effectiveness of ETHOXYQUIN and compound 4 have beenexamined in vitro and ex vivo [Tables III, IV]. In particular, compound4 exhibits a lower oxidation potential and superior LDL protectivecapacity over standard reference agents.

The results to the above tests demonstrates that the compounds ofFormula IV inhibit HMGR activity which results in a decrease in serumtotal cholesterol and LDL cholesterol levels, and inhibit the oxidationof LDL.

Thus, the compounds of Formula IV may be readily administered, to treathypercholesterolemia, hyperlipidemia, and atherosclerosis, and toinhibit LDL oxidation in avian and mammalian systems in need of suchtreatment. For this purpose, the drug may be administered byconventional routes including, but not limited to, the alimentary canalin the form of oral doses, or by injection in sterile parenteralpreparations.

In yet another aspect, the present invention provides a pharmaceuticalcomposition which comprises a compound of Formula IV and a non-toxicpharmaceutically acceptable carrier. These carriers can be solid orliquid such as cornstarch, lactose, sucrose, olive oil or sesame oil. Ifa solid carrier is used, the dosage forms may be tablets, capsules,powders, troches or lozenges. If the liquid form is used, soft gelatincapsules, syrup or liquid suspensions, emulsions, or solutions inconvenient dosage forms may be used. The composition may be made up ofany pharmaceutical form appropriate for the desired route ofadministration. Examples of such compositions include solid compositionsfor oral administration such as tablets, capsules, pills, powders andgranules, liquid compositions for oral administration such as solutions,suspensions, syrups or elixirs and preparations for parenteraladministration such as sterile solutions, suspensions or emulsions. Theymay also be manufactured in the form of sterile solid compositions whichcan be dissolved in sterile water, physiologically saline or some othersterile injectable medium immediately before use.

The dosage ranges will commonly range from about 50 mg to about 200 mg.Optimal dosages and regimes for a given host can be readily ascertainedby those skilled in the art. It will, of course, be appreciated that theactual dose used will vary according to the particular compositionformulated, the particular compound used, the disease being treated.Many factors that modify the action of the drug will be taken intoaccount including age, weight, sex, diet, time of administration, routeof administration, rate of excretion, condition of the patient, drugcombinations, reaction sensitivities and severity of the disease.

All publications cited in this specification are indicative of the levelof skill of those skilled in the art to which this invention pertains.Each publication is individually incorporated herein by reference in thelocation where it is cited.

The following examples are intended for illustrative purpose only andare not to be construed as limiting the invention in sphere or scope.

Melting points were recorded on a Thomas-Hoover melting point apparatusand are uncorrected. Boiling points are uncorrected. Infrared spectrawere obtained on a Perkin-Elmer Model 1800 FT-IR spectrophotometer. ¹H-NMR spectra were recorded on a Bruker AM 300 spectrometer or a VarianGemini 300 NMR spectrometer; nuclear magnetic resonance (NMR) spectralcharacteristics refer to chemical shifts (δ) expressed in parts permillion (ppm) with tetramethylsilane (TMS) as an internal standard. Therelative area reported for the various shifts in the proton NMR spectraldata corresponds to the number of hydrogen atoms of a particularfunctional type in the molecule. Mass spectra were measured on aFinnegan 4500 spectrometer (low resolution).

Thin-layer chromatography was performed on silica gel 60 F-254 platespurchased from E. Merck and company (visualization with iodine orphosphomolybdic acid); flash chromatography was performed on fine silica(EM Sciences, 230-240 mesh). All reactions were run under dry nitrogenunless otherwise indicated. Dry solvents were purchased from Aldrich,Milwaukee, Wisc. in sure/seal bottles and transferred by syringe undernitrogen. Most commercially available starting materials did not requirefurther purification.

EXAMPLE 1 6-Hydroxy-1,2-Dihydro-2,2,4-Trimethylquinoline, (2)

6-Ethoxy-2,2,4-trimethyl-3,4-dihydroquinoline [Ethoxyquin (70 g, 0.32mole)], was added to 250 mL of 48% HBr, and the mixture was heated toreflux for about 1 hour. The solution was cooled and poured into water.The aqueous suspension was made basic (pH=14) by the addition of 50%aqueous NaOH. Concentrated HCl was added to adjust the pH to about 4,then the mixture was made slightly basic by the addition of saturatedsodium bicarbonate solution. The mixture was extracted with EtOAc andthe organic layers were dried (brine, MgSO₄) and concentrated in vacuo.The thick dark oil was triturated with toluene and the insoluble residuewas filtered. The crude solid was recrystallized from toluene to givethe title compound as a light brown solid (mp 182°-184°, 34 g, 0.18mole, 56%). An analytical sample was prepared by anotherrecrystallization from toluene to provide light brown crystals, mp182°-184°: IR (KBr) 3302, 2972, 2934, 1586, 1495, 1344, 1244, 1154, 880,814 cm⁻¹ ; ¹ H NMR (D-6 DMSO) δ 1.12 (s, 6H), 1.33 (s, 3H), 3.34 (s,1H), 5.17 (br s, 1H), 5.26 (s, 1H), 6.28-6.42 (m, 3H); MS m/e 190 (MH⁺).

Anal. Calcd. for C₁₂ H₁₅ N₁ O₁ :

C, 76.16; H, 7.99; N, 7.40.

Found: C, 76.29; H, 7.95; N, 7.37.

EXAMPLE 2 1-Acetyl-6-Hydroxy-1,2-Dihydro-2,2,4-Trimethylquinoline, (3)

6-Hydroxy-1,2-dihydro-2,2,4-trimethylquinoline (12 g, 0.064 mole), andsodium acetate (10.4 g, 0.13 mole) were stirred in 75 mL of aceticanhydride at 100° for about 3 hours. The mixture was poured into waterand extracted into ether. The ether extracts were combined andsuccessively washed with water, aqueous NaHCO₃, dried (brine, MgSO₄) andconcentrated in vacuo. Purification of the crude material by flashchromatography [5:1 Hexanes:Et₂ O] yielded the diacetyl derivative as adark yellow oil: ¹ H NMR (CDCl₃) δ 1.48 (s, 6H), 1.95 (s, 3H), 2.12 (s,3H), 2.27 (s, 3H), 5.51 (s, 1H), 6.76-6.90 (m, 3H).

The diacetyl derivative (12 g) was dissolved in 100 mL of ether. Theether solution was cooled to about -78° and 1M KOH/MeOH (20 mL) wasadded. The reaction mixture was stirred at -78° for about 1 hour atwhich time TLC indicated the reaction to be complete. The solution waspoured into 1N HCl and extracted into ether. The ether extracts weredried (brine, MgSO₄) and concentrated in vacuo. The resulting solid wasrecrystallized from acetonitrile to give the title compound as an offwhite solid (mp 214°-216°, 5.9 g, 0.026 mole, 40%): IR (KBr) 3126, 2972,1626, 1596, 1460, 1368, 1344, 1252, 1218, 868 cm⁻¹ ; ¹ H NMR (CDCl₃) δ1.20 (s, 6H), 1.70 (s, 3H), 1.80 (s, 3H), 5.23 (s, 1H), 6.34-6.44 (m,3H), 8.61 (s, 1H); MS m/e 232 (MH⁺).

Anal. Calcd. for C₁₄ H₁₇ N₁ O₂ :

C, 72.70; H, 7.41; N, 6.06.

Found: C, 72.89; H, 7.46; N, 6.09.

EXAMPLE 31-Acetyl-1,2-Dihydro-2,2,4-Trimethyl-6-[(5,9,13-Trimethyl-4(E),8(E),12-tetradecatrienyl)oxy]Quinoline,(Scheme I)

1-Acetyl-6-hydroxy-1,2-dihydro-2,2,4trimethylquinoline (4.0 g, 17.3mmole), farnesyl ethanol^(1b) (4.3 g, 17.3 mmole), andtriphenylphosphine (5.0 g, 19.0 mmole) were dissolved in 30 mL of THF.Diethylazodicarboxylate (3.3 g, 19.0 mmole) was added dropwise over 5minutes, and the solution was stirred at about 23° for about 40 hours.The volatile components were removed in vacuo and the oily solid wastriturated with ether. The solid was removed by filtration and theresidue was purified by flash chromatography [gradient 6:1 to 5:1Hexanes:Ether] to yield the title compound as a yellow oil (6.1 g, 13.2mmole, 76%): IR (film) 2924, 1672, 1606, 1492, 1364, 1324, 1204 cm⁻¹ ; ¹H NMR (CDCl₃) δ 1.50 (s, 6H), 1.59 (s, 6H), 1.61 (s, 3H), 1.68 (s, 3H),1.83 (m, 2H), 1.94-2.14 (m, 8H), 2.01 (s, 3H), 2.11 (s, 3H), 2.17 (m,2H), 3.95 (t, J=6.4 Hz, 2H), 5.08-5.19 (m, 3H), 5.54 (s, 1H), 6.65-6.79(m, 3H); MS m/e 464 (MH⁺).

Anal. Calcd. for C₃₁ H₄₅ N₁ O₂ :

C, 80.30; H, 9.78; N, 3.02.

Found: C, 80.03; H, 9.70; N, 3.04.

EXAMPLE 4 1,2-Dihydro-2,2,4-Trimethyl-6-[(5,9,13-Trimethyl-4(E), 8(E),12-tetradecatrienyl)oxy]Quinoline, (4) ##STR9##

1-Acetyl-1,2-dihydro-2,2,4-trimethyl-6-[(5,9,13-trimethyl-4(E), 8(E),12-tetradecatrienyl) oxy]quinoline (8.2 g, 17.7 mmole) was dissolved in75 mL of THF and the solution was cooled to about -10°. Lithiumtriethylborohydride (1.0M, 89 mL, 89 mmole) was added dropwise to themixture end the cooling bath was removed. After stirring at about 23°for about 60 hours, the reaction was quenched by the careful addition ofsaturated NH4Cl solution. The mixture was poured into water andextracted into ether. The ether extracts were dried (brine, MgSO₄) andconcentrated in vacuo. Purification of the crude material by flashchromatography [20:1 Hexanes:Et₂ O] yielded the dihydroquinoline as ayellow oil (6.2 g, 12. 8 mmole, 72%): IR (film) 3364, 2964, 1650, 1580,1498, 1446, 1380, 1260, 1156 cm⁻¹ ; ¹ H NMR (CDCl₃ +TFA) δ 1.50 (s, 6H),1.57 (s, 6H), 1.59 (s, 3H), 1.65 (s, 3H), 1.85 (m, 2H), 1.94-2.14 (m,8H), 2.07 (s, 3H), 2.16 (m, 2H), 3.94 (t, J=6.3 Hz, 2H), 5.0 (m,3H),5.63 (s, 1H), 6.76 (d of d, J=2.5, 8.6 Hz, 1H), 6.88 (d, J=2.5 Hz, 1H),7.32 (d, J=8.6 Hz, 1H); MS m/e 422 (MH⁺).

Anal. Calcd. for C₂₉ H₄₃ N₁ O₁ :

C, 82.61; H, 10.28; N, 3.32.

Found: C, 82.71; H, 10.40; N, 3.21.

EXAMPLE 5 O-[1,2-Dihydro-2,2,4-Trimethylguinoline]Dimethylthiocarbamate,(5)

6-Hydroxy-1,2-dihydro-2,2,4-trimethylquinoline (6 g, 31.7 mmole) anddimethylthiocarbamoyl chloride (5.2 g, 42.3 mmole) were dissolved in 50mL of DMF. The mixture was cooled to about 0° and sodium hydride (1.3 g,31.7 mmole, 60%) was added portionwise. The mixture was warmed to about60° until complete by TLC (1 hour). The solution was poured into waterand the solid was collected by filtration to yield the title compound asbrown solid (mp 125-128, 8.0 g, 29 mmole, 92%). A portion of thematerial was recrystallized from toluene/hexanes for analysis (paleamber crystals, mp 128°-130°): IR (KBr) 3322,2962, 1536, 1496, 1482,1394, 1288, 1254, 1194, 1154, 880, 814 cm⁻¹ ; ¹ H NMR (CDCl₃) δ 1.25 (s,6H), 1.92 (s, 3H), 3.29 (s, 3H), 3.43 (s, 3H), 5.29 (s, 1H), 6.37 (d,J=8.2 Hz, 1H), 6.65 (d of d, J=8.2,2.6 Hz, 1H), 6.70 (d, J=2.6 Hz, 1H);MS m/e 277 (MH⁺).

Anal. Calcd. for C₁₅ H₂₀ N₂ O₁ S₁ :

C, 65.18; H, 7.29; N, 10.14.

Found: C, 65.53; H, 7.36; N, 9.82.

EXAMPLE 6 S-[1,2-Dihydro-2,2,4-Trimethylquinoline]Dimethylthiocarbamate,(Scheme II)

p-Toluenesulfonic acid monohydrate (550 mg, 2.9 mmole) was heated undervacuum (15 mm) for about 3 hours at about 150° to remove water.O-[1,2-Dihydro-2,2,4-trimethylquinoline] dimethylthiocarbamate 5 (4 g,14.5 mmole) was added to the cooled acid, and the mixture was slowlyheated under 15 mm of pressure to 180°-200° at which time the componentsbecame a homogeneous melt. The vessel was pressurized with nitrogen (1atm). The mixture was then heated at about 207° for about 1 hour, atwhich time TLC indicated the conversion to be approximately 75%complete. The reaction mixture was cooled and dissolved into ethylacetate. The solution was treated with activated carbon, filtered andconcentrated in vacuo. Purification of the crude material by flashchromatography [gradient 4:1 to 2:1 Hexanes:Et₂ O] yielded thedihydroquinoline as an amber solid (2.4 g, 8.7 mmole, 60%). A sample wasrecrystallized from toluene/hexanes for analysis (pale amber crystals,mp 89°-90°): IR (KBr) 3332,2970, 1651, 1596, 1488, 1448, 1362, 1260,1102, 1092, 828 cm⁻¹ ; ¹ H NMR (CDCl₃) δ 1.27 (s, 6H), 1.96 (s, 3H),3.04 (br s, 6H), 5.31 (s, 1H), 6.56 (d, J=1.7 Hz, 1H), 6.72 (d of d,J=9.0, 1.7 Hz, 1H), 6.7.03 (d, J=9.0 Hz, 1H); MS m/e 277 (MH⁺).

Anal. Calcd. for C₁₅ H₂₀ N₂ O₁ S₁ :

C, 65.18; H, 7.29; N, 10.14.

Found: C, 65.33; H, 7.23; N, 10.04.

EXAMPLE 7 1-Acetyl-S-[1,2-Dihydro-2,2,4-Trimethylquinoline]

S-[1,2-Dihydro-2,2,4-trimethylquinoline] dimethylthiocarbamate (6.5 g,23.6 mmole) and sodium acetate (3.9 g, 47.1 mmole) were stirred in 50 mLof acetic anhydride at reflux for about 3 hours. The mixture was slowlypoured into excess saturated NaHCO₃ solution (caution!). The mixture wasextracted into ethyl acetate, and the organic layers were dried (brine,MgSO₄) and concentrated in vacuo. Purification of the crude solid byrecrystallization from toluene/hexanes provided the N-acetyl derivativeas a pale amber solid, mp 110°-112° (2.2 g, 6.9 mmole, 29%): IR (KBr)2960, 1683, 1651, 1552, 1492, 1474, 1366, 1314, 1242, 1098, 840 cm⁻¹ ; ¹H NMR (CDCl₃) δ 1.48 (s, 6H), 1.97 (s, 3H), 2.18 (s, 3H), 2.99 (br s,6H), 5.49 (s, 1H), 6.92 (d, J=1.2 Hz, 1H), 7.16 (m, 2H); MS m/e 319(MH⁺).

Anal. Calcd. for C₁₇ H₂₂ N₂ O₂ S₁ :

C, 64 . 12; H, 6.96; N, 8.80.

Found: C, 64.19; H, 6.82; N, 8.76.

EXAMPLE 8 1-Acetyl-1,2-Dihydro-2,2,4-Trimethylguinoline-6-Thiol, (7)

1-Acetyl-S-[1,2-dihydro-2,2,4-trimethylquinoline]dissolved in a solutionof sodium methoxide prepared from sodium (360 mg, 15.7 mmole) inmethanol (20 mL). The mixture was stirred for about 48 hours at about23° at which time TLC indicated complete hydrolysis. The mixture waspoured into 1N HCl and extracted into ether. The ether extracts werecombined, dried (brine, MgSO₄) and concentrated in vacuo. Purificationof the crude material by flash chromatography [gradient 5:1 to 4:1Hexanes:Et₂ O] yielded the free thiophenol as a yellow oil (1.4 g, 5.7mmole, 72%): ¹ H NMR (CDCl₃) δ 1.48 (s, 6H), 1.96 (s, 3H), 2.16 (s, 3H),5.45 (s, 1H), 6.73 (d, J=1.2 Hz, 1H), 6.98 (d of d, J=1.2, 9.0 Hz, 1H),7.06 (d, J=9.0 Hz, 1H), MS m/e 248 (MH⁺).

EXAMPLE 91-Acetyl-1,2-Dihydro-2,2,4-Trimethyl-6-[(5,9,13-Trimethyl-4(E),8(E),12tetradecatrienyl)thio]

1-Acetyl-1,2-dihydro-2,2,4-trimethylquinoline-6thiol (1.4 g, 5.67mmole), potassium carbonate (1.2 g, 8.5 mmole), and farnesylethyl iodide(2.0 g, 5.67 mmole) were added to 30 mL of acetonitrile. TLC indicatedthe reaction to be complete after stirring for about 30 minutes at about23°. The mixture was poured into water and extracted into ether. Theether extracts were combined, dried (brine, MgSO₄) and concentrated invacuo. Purification of the crude material by flash chromatography [15:1Hexanes:Et₂ O]yielded the title compound as a yellow oil (2.2 g, 4.59mmole, 81%). A small sample was distilled in a Kugelrohr oven (bath180°-190°/0.15 mm) for analysis: IR (film) 2924, 1680, 1594, 1492, 1362,1314 cm⁻¹ ; ¹ H NMR (CDCl₃) δ 1.48 (s, 6H), 1.56 (s, 6H), 1.58 (s, 3H),1.64 (s, 3H), 1.65 (m, 2H), 1.90-2.15 (m, 10H), 1.98 (s, 3H), 2.14 (s,3H), 2.86 (t, J=7.1 Hz, 2H), 5.07 (m,3H), 5.45 (s, 1H), 6.75 (d, J=1.7Hz, 1H), 7.02 (d of d, J=1.7, 11 Hz, 1H), 7.06 (d, J=11.0 Hz, 1H); MSm/e 480 (MH⁺).

Anal. Calcd. for C₃₁ H₄₅ N₁ O₁ S₁ :

C, 77.61; H, 9.45; N, 2.92.

Found: C, 77.31; H, 9.38; N, 2.88.

EXAMPLE 10 1,2-Dihydro-2,2,4-Trimethyl-6-[(5,9,13-Trimethyl-4(E),8(E),12-tetradecatrienyl)thio]Quinoline, (8) ##STR10##

1-Acetyl-1,2-dihydro-2,2,4-trimethyl-6-[(5,9,13-trimethyl-4 (E), 8 (E),12-tetradecatrienyl)thio]quinoline (1.9 g, 3.97 mmole) was dissolved in20 mL of THF and the solution was cooled to about -10°. Lithiumtriethylborohydride (1.0M, 19.8 mL, 19.8 mmole) was added dropwise tothe mixture and the cooling bath was removed. After stirring at about23° for about 15 hours, the reaction was quenched by the carefuladdition of saturated NH₄ Cl solution. The mixture was poured into waterand extracted into ether. The ether extracts were dried (brine, MgSO₄)and concentrated in vacuo. Purification of the crude material by flashchromatography [20:1 Hexanes:Et₂ O]yielded the dihydroquinoline as ayellow oil (1.3 g, 2.97 mmole, 75%): IR (film) 3372,2964, 1652, 1598,1448, 1258, 1168 cm⁻¹ ; ¹ H NMR (CDCl₃) δ 1.26 (s, 6H), 1.59 (s, 9H),1.65 (m, 2H), 1.67 (s, 3H), 1.95 (s, 3H), 1.95-2.15 (m, 10H), 2.16 (m,2H), 2.86 (t, J=7.2 Hz, 2H), 3.72 (br s, 1H), 5.08 (m,3H), 5.26 (s, 1H),6.40 (d, J=1.8 Hz, 1H), 6.57 (d of d, J=8.0, 1.8 Hz, 1H), 6.94 (d, J=8.0Hz, 1H); MS m/e 438 (MH⁺).

Anal. Calcd. for C₂₉ H₄₃ N₁ S₁ :

C, 79.57; H, 9.90; N, 3.20.

Found: C, 79.61; H, 9.61; N, 3.24.

EXAMPLE 11 4-Methyl-1-[[[4-Nitrophenyl]methyl]sulfonyl]benzene, (SchemeIII)

4-Nitrobenzyl chloride (5.0 g, 29.1 mmole) and sodium p-toluenesulfinate(6.8 g, 37.9 mmole) were dissolved in 50 mL of dry DMF. The mixture wasstirred at about 23° for about 18 hours then diluted with water. Thesulfone crystallized from the aqueous mixture and was filtered. Thesulfone was purified by recrystallization from ethanol to give a paleyellow crystalline solid, mp 188°-190° (7.6 g, 25.9 mmole, 89%): IR(KBr) 2994, 1598, 1514, 1490, 1342, 1312, 1304, 1148, 824 cm⁻¹ ; ¹ H NMR(CDCl₃) δ 2.44 (s, 3H), 4.38 (s, 2H), 7.27 (m, 4H), 7.53 (d, J=8.3 Hz,2H), 8.13 (d, J=8.3 Hz, 2H); MS m/e 292 (MH⁺).

Anal. Calcd. for C₁₄ H₁₃ N₁ O₄ S₁ :

C, 57.72; H, 4.50; N, 4.81.

Found: C, 57.72; H, 4.46; N, 4.80.

EXAMPLE 12 4-[[[(4-Methylphenyl)sulfonyl]methyl]Aniline, (9)

A solution of 4-methyl-1-[[[4-nitrophenyl]methyl]sulfonyl] benzene (15g, 51 mmol) in ethanol (250 mL) containing stannous chloride dihydrate(57.5 g, 255 mmol) was heated to reflux for about 3 hours. The mixturewas cooled, poured into water and neutralized with 20% aqueous sodiumhydroxide. The solution was filtered and dried under aspirator vacuum.The pale yellow solid was washed with hot ethyl acetate (3 L) and thesolvent removed in vacuo to give 3 as white needles (13.4 g, 5.1 mmole,75%) mp 217°-218°: IR (KBr) 3444, 3370, 1636, 1612, 1294, 1284, 1142cm⁻¹ ; ¹ H NMR (CDCl₃) δ 2.40 (s, 3H), 3.70 (s, exchanges with D₂ O,2H), 4.16 (s, 2H), 6.54 (d, J=8.5 Hz, 2H), 6.83 (d, J=8.5 Hz, 2H), 7.22(d, J=6.4 Hz, 2H), 7.50 (d, J=6.4,2H); MS m/e 261 (M⁺).

Anal. Calcd. for C₁₄ H₁₅ N₁ O₂ S₁ :

C, 64.34; H, 5.78; N, 5.36.

Found: C, 64.50; H, 5.79; N, 5.32.

EXAMPLE 131,2-Dihydro-2,2,4-Trimethyl-6-[1-(4Methylphenyl)sulfonyl]Quinoline, (10)

A solution of 4-[[(4methylphenyl)sulfonyl]methyl] aniline (3.1 g, 10.6mmol) in dioxane (150 mL) containing I₂ (160 mg, 0.6 mmol) was heated toabout 90° C. and acetone(250 mL) was added dropwise such that adistillation rate of 1-2 drops/sec is maintained. After about 6 hours,acetone (100 mL) was added and the reaction mixture was refluxedovernight. The above sequence was repeated over a 12 hour period. Thereaction mixture was cooled, concentrated and the black viscous oil waspurified by flash chromatography with 30% ethyl acetate in hexanes aseluant to give the title compound as a pale yellow solid (2.17 g , 6.4mmole, 52%) which can be further purified by recrystallization fromethyl acetate-ether to give a white solid mp 134°-135°: IR (KBr) 3380,1375, 1300, 1140, 815 cm⁻ ; ¹ H NMR (CDCl₃) δ 1.24 (s, 6H), 1.77 (s,3H), 2.39 (s, 3H), 3.77 (s, exchanges with D₂ O, 1H), 4.13 (s, 2H), 5.26(s, 1H), 6.30 (d, J=8.0 Hz, 1H) 6.57 (s, 1H), 6.69 (dd, J=1.8, 6.3 Hz,1H), 7.23 (d, J=8.3 Hz, 2H), 7.52 (d, J=8.3 Hz, 2H); MS m/e 341 (M⁺).

Anal. Calcd for C₂₀ H₂₃ N₁ O₂ S₁ :

C, 70.35; H, 6.79; N, 4.10.

Found: C, 70.37; H, 6.81; N, 4.04.

EXAMPLE 14N-Acetyl-1,2-Dihydro-2,2,4-Trimethyl-6-[1-(4methylphenyl)sulfonyl]Quinoline,(Scheme III)

A solution of1,2-dihydro-2,2,4-trimethyl-6-[1(4-methylphenyl)sulfonyl]quinoline (3.4g, 10 mmol) in acetic anhydride (9.6 mL, 100 mmol) containing sodiumacetate (0.9 g, 11 mmol) was heated to reflux for about 1 hour, thenstirred overnight at about 23°. The reaction is not complete asindicated by TLC analysis. Additional acetic anhydride (5 mL) was addedand the mixture was heated to reflux for about 2 hours then cooled. Thereaction mixture was poured into dilute sodium hydroxide (10%) and theaqueous layer extracted with ether. The ether extracts were dried(brine, MgSO₄) and concentrated in vacuo. The residue was purified byflash chromatography using 50% ethyl acetate in hexanes as an eluant togive N-acetyl derivative (3.19 g, 8.3 mmole, 83%) as a yellow oil: IR(film) 3018,2972,2926, 1675, 1315, 1150, 825 cm⁻¹ ; ¹ H NMR (CDCl₃) δ1.48 (s,6H), 1.86 (s, 3H), 2.11 (s, 3H), 2.40 (s, 3H), 4.24 (s, 2H),5.48(s, 1H), 6.70-6.67(m, 1H), 6.85-6.81(m, 2H), 7.49(d, J=8.4 Hz, 2H),7.51(d, J=8.4 Hz, 2H); MS m/e 383 (M⁺).

EXAMPLE 15 N-Acetyl-1,2-Dihydro-2,2,4-Trimethyl-6-[1-f(4-Methylphenyl)sulfonyl)-6,10,14-Trimethyl-5 (E), 9 (E), 13Pentadecatrienyl] Quinoline,(Scheme III)

A solution ofN-acetyl-1,2-dihydro-2,2,4-trimethyl-6-[1-(4-methylphenyl)sulfonyl]quinoline(7.89 g, 23.1 mmol) in THF (100 mL) was cooled to -78°, and treated withpotassium bis(trimethylsilyl)amide (46.2 mmol, 23.1 mmol, 0.5 M intoluene) and stirred for about 15 minutes. DMPU (26 mL) was added to thereaction mixture followed by a solution of farnesylethyl iodide (8.2 g,23.1 mmol) in THF (25 mL). The reaction mixture was stirred for about 1hour at about -78° then poured into water (100 mL), and the aqueouslayer was extracted with ether. The organic extracts were combined,dried (brine, MgSO₄) and concentrated in vacuo. The residue was purifiedby flash chromatography using 20% ethyl acetate in hexanes as an eluantto give the alkylated sulfone as a yellow oil (8.13 g, 13.2 mmole, 57%):IR (film) 2926, 1675, 1320, 1150, 820 cm⁻¹ ; ¹ H NMR (CDCl₃) δ 1.34-1.22(m, 4H), 1.48 (s, 6H), 1.52 (s, 3H), 1.55 (s, 3H), 1.57 (s, 3H), 1.68(s, 3H), 1.81 (s, 3H), 1.93-2.10 (m, 10H), 2.10 (s, 3H), 2.35 (s, 3H),3.98 (dd, J=3.9, 11.5 Hz, 1H), 4.98-5.07 (m, 3H), 5.47 (s, 1H), 6.92 (d,J=8.2 Hz, 1H), 7.02-7.05 (m, 2H), 7.14 (d J=8.11 Hz, 2H), 7.38 (d, J=8.1 Hz, 2H); MS m/e 615 (M⁺).

Anal. Calcd for C₃₉ H₅₃ N₁ O₃ S₁ :

C, 76.05; H, 8.67; N, 2.28.

Found: C, 76.15; H, 8.68; N, 2.30.

EXAMPLE 16N-Acetyl-1,2-Dihydro-2,2,4-Trimethyl-6-[6,10,14-Trimethyl-5(E),9(E),13-Pentadecatrienyl]Quinoline,(Scheme III)

A mixture ofN-acetyl-1,2-dihydro-2,2,4-trimethyl-6-[1-((4-methylphenyl)sulfonyl)-6,10,14-trimethyl-5(E), 9(E), 13-pentadecatrienyl]quinoline (8.1 g, 13.2 mmol) and disodiumhydrogen phosphate (7.5 g, 53 mmol) in methanol (50 mL) were cooled toabout 0°. Sodium amalgam (10 mesh, 6% Na, 18.6 g) was added, and afterabout 30 minutes, the reaction mixture was warmed to 23° C. and stirredfor an additional 12 hours. The reaction mixture was poured into water(50 mL) and the aqueous layer extracted with ether. The ether extractswere combined, dried (brine, MgSO₄) and concentrated in vacuo. Theresidue was purified by flash chromatography [gradient 10:1 to 5:1Hexanes:EtOAc] to give the N-acetyl derivative as a clear oil (3.48 g,7.5 mmole, 57%): IR (film) 2965-2854, 1678, 1450, 823 cm⁻¹ ; ¹ H NMR(CDCl₃) δ 1.28-1.41 (m, 2H), 1.44 (s, 6H), 1.53 (s, 12H), 1.61 (s, 3H),1.84-1.97 (m, 12H), 2.08 (s, 3H), 2.54 (t, J=7.6 Hz, 2H), 4.99-5.09 (m,3H), 5.43 (s, 1H), 6.69 (d, J=8.0 Hz, 1H), 6.92 (d, J=8.0 Hz, 1H) 6.94(s, 1H); MS m/e 461 (M⁺).

Anal. Calcd for C₃₂ H₄₇ N₁ O₁ :

C, 83.24; H, 10.26; N, 3.03.

Found: C, 83.64; H, 10.40; N, 3.05.

EXAMPLE 17 1,2-Dihydro-2,2,4-Trimethyl-6-[6,10,14-Trimethyl5(E),9(E),13-Pentadecatrienyl]Quinoline, (11) ##STR11##

Lithium triethylborohydride (22.7 mL, 22.7 mmol, 1.0 M in THF) was addedto a solution of the acetamide (3.48 g, 7.56 mmol) maintained at about0° in THF (50 mL). The reaction was slowly warmed to about 23° andstirred for about 12 hours. The reaction mixture was poured into water(100 mL) and the aqueous layer extracted with ethyl acetate. The organicextracts were combined, dried (brine, MgSO₄) and concentrated in vacuo.The residue was purified by flash chromatography [20:1 Hexanes: EtOAc]to give in order of elution: Compound of example (11)(1.28 g, 3.1 mmole,40%) and the starting material (1.42 g, 3.1 mmole, 41%): IR (film)3380,2900, 1450, 1380, 810 cm⁻¹ ; ¹ H NMR (CDCl₃) δ 1.25 (s, 6H), 1 17-142 (m, 4 H), 1.42-1.59 (m, 12H), 1.68 (s, 3H), 1.98 (s, 6 H), 1.96-2.04(m, 4 H), 2.34 (m, J=7.2 Hz, 2H), 3.54 (br s, exchanges with D₂ 0, 1H),5.07-5.12 (m, 3H), 5.29 (s, 1H), 6.36 (d, J=7.8 Hz, 1H), 6.86 (d, J=7.9Hz, 1H), 6.86 (s, 1H); MS m/e 419 (M⁺).

Anal. Calcd for C₃₀ H₄₅ N₁ :

C, 85.86; H, 10.81; N, 3.34.

Found: C, 85.87; H, 10.82; N, 3.23.

EXAMPLE 18 [4-(1,1-dimethylethyl)dimethylsilyloxy]butana], C12) andethyl 2-methyl-6-[(1,1-dimethylethyl)dimethylsilyloxy]-2(E)-hexenoate,(13)

To a solution of 5-methyl-4-hexenal (Marbet, et al., Helv. Chim. Acta.,50: 2095-3000 (1967)) (18.8 g, 168 mmol) in ethanol (100 mL) at 0° isadded dropwise a solution of sodium borohydride (1.7 g, 46.2 mmol) inmethanol (100 mL). The reduction is complete in about 30 minutes asindicated by TLC analysis. The reaction mixture is neutralized withdiluted aqueous acetic acid (10%), then poured into water and theaqueous layer extracted with ether. The ether extracts are washed withwater, dried (brine, MgSO₄) and concentrated to give the alcohol (13.89g, 122 mmol, 57%) as a clear oil (bp 108°-120°/0.25 mm Hg).

A solution of alcohol (13.9 g, 122 mmol) in DMF (100 mL),tert-butyldimethylsilyl chloride (20.1g, 134 mmol) and imidazole (9.95g,146 mmol) is stirred at about 23° for about 24 hour. The reactionmixture is poured into water and the aqueous layer extracted with ether.The ether extracts are washed with water, dried (brine, MgSO₄) andconcentrated. The residue is purified by flash chromatography usinghexanes as eluant to give the silyl ether (17.9 g, 64%, 78.5 mmol) as aclear oil (bp 57°-60° C./0.25 mmHg): IR(film) 2956,2930,2888, 1380,1250, 1100, 840 cm⁻¹ ; ¹ H NMR(CDCl₃) δ 0.042 (s, 6H), 0.89 (s, 9H),1.54 (d of t, J=8.17, 7.0 Hz,2H), 1.59 (s, 3H), 1.67 (s, 3H), 2.02 (dd,J=7.3, 14.8 Hz, 2H), 3.59 (t, J=6.5 Hz, 2H), 5.11 (t, J=7.2 Hz, 1H); MS228 (M⁺).

Anal. Calcd. for C₁₃ H₂₈ OSi:

C, 68.35; H, 12.35.

Found: C, 68.66; H, 12.50.

A solution of the silyloxyolefin (2.0 g, 8.8 mmol) in dichloromethane(50 mL) is cooled to about -78° and ozone is bubbled through thesolution until a light blue color remains. The ozone flow is turned offand nitrogen is bubbled through the solution until the ozone colorfades. Dimethyl sulfide (1.9 mL, 36.4 mmol) is added and the mixturestirred at about -78° for about 1 hour and at about 23° for about 2hours. (Note: The aldehyde 12 decomposed during an attempteddistillation thus the aldehyde was not isolated.) To the reactionmixture is added (carbethoxyethylidene) triphenylphosphorane (3.3 g, 8.8mmol) and the yellow solution is stirred for about 2 hours. Although theyellow color of the phosphorane is gone after about 2 hours, TLCanalysis indicates some aldehyde remains. Additional phosphorane (0.5 g,1.4 mmol) is added and the reaction mixture is stirred for about 48hours at about 23°. The reaction mixture is concentrated, trituratedwith pentane, filtered, concentrated and the residue purified by flashchromatography to give 13 (2.3295 g, 93%, 8 1 mmol) as a clear oil: IR(film) 1710, 1370, 1260, 1100, 840 cm⁻¹ ; ¹ H NMR (CDCl₃) δ 0.023 (s,6H), 0.87 (s, 9H), 1.26 (t, J=7.1 Hz, 3H), 1.62(dt, J=14.6, 6.2 Hz, 2H),1.80 (s, 3H), 2.22 (q, J=7.4, 14.9 Hz, 2H), 3.60 (t, J=6.2 Hz, 2H), 4.15(q, J=7.1, 14.2 Hz, 2H), 6.74 (t, J=7.5 Hz, 1H); MS 286 (M⁺).

Anal. Calcd. for C₁₅ H₃₀ O₃ Si

C, 62.89; H, 10.56.

Found: C, 62.88; H, 10.65.

EXAMPLE 19

2-Methyl-6-[(1,1-dimethylethyl) dimethylsilyloxy]-2(E)-hexenol, (14)

Diisobutylaluminum hydride (42 mL, 42 mmol, 1.0 M in toluene) in THF (50mL) is added to a solution of ester 13 (6.0 g, 21.0 mmol) in THF (50 mL)at about -78° and stirred for about 4 hours. A solution of NaOH (1N, 100mL) is added and the aqueous layer extracted with ether. The etherextracts are combined, washed with saturated aqueous sodium chloride,dried over magnesium sulfate and concentrated. The oily residue ispurified by flash chromatography to give in order of elution (0.12 g,0.49 mmol, 2%) of the Z isomer and 14 (3.677 g, 15.1 mmol, 72%) of amixture of E and Z isomers (E/Z=30.6/1): IR(film) 3335,2900, 1450, 1390,1360, 1250, 1100, 1060, 840 cm⁻¹ ; ¹ H NMR (CDCl₃) δ 0.014 (s, 6H), 0.85(s, 9H), 1.21 (s, 1H, exchanges with D₂ O), 1.53 (dt, J=14.9, 6.4 Hz,2H), 1.62 (s, 3H), 2.04 (dd, J =7.1, 14.8 Hz, 2H), 3.56 (t, J=6.4 Hz,2H), 3.95 (s, 2H), 5.37 (tq, J=1.4, 7.3 Hz, 1H); MS m/e 244 (M⁺).

Anal. Calcd. for C₁₃ H₂₀ O₂ Si

C, 63 . 88; H, 11.55.

Found: C, 64.00; H, 11.54.

EXAMPLE 206-Chloro-1-[(1,1-dimethylethyl)dimethylsilyloxy]-5-methyl-4(E)-hexene,(15)

N-chlorosuccinimide (2.5 g, 18.7 mmol) is dissolved in dichloromethane(100 mL), cooled to about 0° and treated with dimethyl sulfide (1.4 mL,19.5 mmol) and stirred for about 1 hour. The alcohol (3.3 g, 13.5 mmol)is added and the reaction mixture stirred for about 3 hours. The solventis removed in vacuo and the residue purified by flash chromatographywith 10% ethyl acetate in hexanes as eluant. The chloride 15 is isolatedas a clear oil (2.9 g, 11.1 mmol, 82%).

EXAMPLE 21 General Procedure for the Synthesis of Benzyl Sulfones

The commercially available benzyl bromide or benzyl chloride (50 mmole)and sodium p-toluenesulfinate (65 mmole) were dissolved in 50-100 mL ofdry DMF. The mixtures were stirred at about 23° for about 18 hours thendiluted with water. In most cases the sulfones crystallized from theaqueous mixture and were filtered, if not, they were extracted intoether. The compounds were purified by recrystallization (EtOH) or columnchromatography.

4-Methyl-1-[[[3-(trifluoromethyl) phenyl]methyl]sulfonyl]benzene

Colorless plates, mp 139°-140°: IR (KBr) 2954, 1614, 1598, 1450, 1332,1312, 1288, 1164, 1142, 1116, 1074 cm⁻¹ ; ¹ H NMR (CDCl₃) δ 2.44 (s,3H), 4.34 (s, 2H), 7.16 (s, 1H), 7.26 (d, J=8.1 Hz, 2H), 7.42 (m, 1H),7.50 (d, J=8.1 Hz, 2H), 7.58 (d, J=7.5 Hz, 1H); MS m/e 315 (MH⁺).

Anal. Calcd. for C₁₅ H₁₃ F₃ O₂ S₁ :

C, 57.32; H, 4.17.

Found: C, 57.28; H, 4.08.

EXAMPLE 227-[(1,1-Dimethylethyl)dimethylsilyloxy]-3-Methyl-1-[(4-Methylphenyl)sulfonyl]-1-[3(Trifluoromethyl)phenyl]-hept-3(E)-ene , (16)

4-Methyl-1-[[[3-(trifluoromethyl)phenyl]methyl]sulfonyl]benzene (2.8 g,8.9 mmol) in THF (20 mL) is cooled to about -78°, treated with nBuLi(8.9 mL, 8.95 mmol) and stirred for about 1 hour. Dry DMPU (5 mL) isadded followed by a solution of the allylic chloride 15 (1.96 g, 7.48mmol) in THF (10 mL). The mixture is warmed to about 0° and stored forabout 48 hours. The reaction is poured into water (50 mL) and extractedwith ether. The ether extracts are dried (MgSO₄) and concentrated. Theresidue is purified by flash chromatography with 10% ethyl acetate inhexanes as eluant to give 16 (2.60 g, 4.81 mmol, 65%) as a white solid(mp 80°-85°): IR (KBr) 1330, 1300, 1160, 1140, 1125, 1100, 840, 775 cm⁻¹; ¹ H NMR (CDCl₃) δ 0.06 (s, 6H), 0.80 (s, 9H), 1.14-1.31 (m, 2H), 1.44(s, 3H), 1.80 (dd, J=14.6, 7.3 Hz, 2H), 2.35 (s, 3H), 2.78 (dd, J=12.2,13.8 Hz, 1H), 3.05 (d, J=13.9 Hz, 1H), 3.10-3.31 (m, 2H), 4.22 (dd,J=3.7, 12.1 Hz, 1H), 5.02 (t, J=7.2 Hz, 1H), 7.09-7.16 (m, 3H),7.35-7.37 (m, 4H) 7.46-7.48 (m, 1H); MS 540 m/e (M⁺).

Anal. Calcd. for C₂₈ H₃₉ O₃ SF₃

C, 62.19; H, 7.27.

Found: C, 62.13; H, 7.22.

EXAMPLE 23 3-[3-Methyl-7-iodo-3(E)-hexenyl]-1-trifluoromethyl benzene,(17)

To a solution of sulfone 16 (2.6 g, 4.8 mmol) at 0° in methanol (50 mL)containing Na₂ HPO₄ (2.67 g, 18.8 mmoL) is added sodium amalgam (6%sodium). The reaction mixture is warmed to about 23° and stirred forabout 4 hours then poured into water and the aqueous layer extractedwith ether. The organic extracts are dried (brine, MgSO₄) andconcentrated. The remaining clear oil is purified by columnchromatography with 10% ethyl acetate in hexanes as eluant to give inorder of elution the desulfonylated material (1.40 g, 3.63 mmol, 76%) asa clear oil and unreacted starting material 16 (0.47 g, 0.87 mmol, 18%).

The silyl ether (3.5 g, 9.1 mmol) is dissolved in THF (20 mL) andtreated with tetrabutylammonium fluoride (15 mL, 15.0 mmol, 1.0 M inTHF) and stirred at about 23° for about 1 hour. The reaction mixture ispoured into water and the aqueous layer is extracted with ether. Theether extracts are combined, dried over magnesium sulfate andconcentrated. The remaining clear oil can be purified by flashchromatography with 15% ethyl acetate in hexanes as eluant followed by20% ethyl acetate in hexanes to give the alcohol (1.6 g, 5.88 mmol, 73%)as a clear oil: IR(film) 3340, 1450, 1325, 1160, 1125, 1075, 795 cm⁻¹ ;¹ H NMR (CDCl₃) δ 1.23 (t, J=5.0 Hz, 1H, exchanges with D₂ O), 1.54 (dt,J=14.4, 7.1 Hz, 2H); 1.64(s, 3H), 2.03 (dd, J=7.2, 14.6 Hz, 2H), 2.27(t, J=8.3 Hz, 1H), 2.74 (t, J=7.8 Hz, 2H), 3.54 (m, 2H), 5.08 (t, J=7.2Hz, 1H), 7.30-7.42 (m, 2H); MS 272 m/e (M⁺).

Anal. Calcd. for C₁₅ H₁₉ OF₃ C, 66.16; H, 7.03.

Found: C, 66.12; H, 6.99.

A solution of the alcohol (2.0 g, 7.35 mmol) in dichloromethane (10 mL)at 0° is treated with triethylamine (1.03 ml, 8.1 mmol) thenmethanesulfonyl chloride (0.59 mL, 7.72 mmol). The reaction mixture iswarmed to about 23° and stirred for about 12 hours. The reaction mixtureis poured into water and the aqueous layer extracted withdichloromethane. The dichloromethane extracts are dried over magnesiumsulfate and concentrated to give the mesylate (2.24 g, 87%, 6.4 mmol) asa clear oil. The oil is dissolved in acetone, NaI (11.0 g, 73.5 mmol) isadded and the reaction mixture is heated to reflux for about 2 hours.The mixture is cooled, poured into water and the aqueous layer extractedwith ether. The organic extracts are dried (MgSO₄) and concentrated togive the iodide 17 (2.24 g, 5.86 mmol, 80%) as a dark red oil.

EXAMPLE 241,2-dihydro-2,2,4-trimethyl-6-[[5-methyl-7-[3(trifluoromethyl)phenyl]-4(E)-hexenyl]oxy]quinoline, (18) ##STR12##

A mixture of phenol 3 (1.2 g, 5.2 mmol), iodide 17 (2.24 g, 5.86 mmol)and K₂ CO₃ (4.0 g, 29.3 mmoL) in DMF (20 mL) is stirred at about 23° forabout 1 hour then at about 50° for about 12 hours and at about 90° forabout 1 hour. The reaction mixture is cooled, poured into water and theaqueous layer extracted with ethyl acetate. The ethyl acetate extractsare dried over magnesium sulfate and concentrated. The resulting yellowoil is chromatographed to give the Nacetyl derivative (1.72 g, 60%, 3.59mmol) as a yellow oil contaminated with 0.45 g of an unknown oil thatdoes not interfere with the next reaction: IR (film) 1710, 1670, 1360,1325, 1200, 1160, 1125, 850 cm⁻¹ ; NMR (CDCl₃) δ 1.48 (s, 6H), 1.64 (s,3H), 1.75 (dt, J =6.9, 13.6 Hz, 2H), 1.98 (s, 3H), 2.10 (s, 3H), 2.13(q, J=7.6, 14.8 Hz, 2H), 2.28 (t, J=7.8 Hz, 2H), 2.75 (t, J=7.4 Hz, 2H),3.85 (t, J=6.3 Hz, 2H), 5.52 (t, J=7.1 Hz, 1H), 6.63 (dd, J=2.8, 8.6 Hz,1H), 6.73-6.77 (m, 2H), 7.29-7.41 (m, 4H); MS 485 m/e (M⁺).

A solution of the acetamide (1.8 g, 3.7 mmol) in THF (40 mL) maintainedat about -78° is treated with LiEt₃ BH (11.1 mL, 11.1 mmol, 1.0M inTHF). The reaction is warmed to about 23° stirred for about 12 hoursthen poured into water (100 mL) and the aqueous solution extracted withether. The ether extracts are dried (MgSO₄) and concentrated. The yellowresidue is purified by column chromatography using 15% ethyl acetate inhexanes as eluant. The free amine is isolated as a light yellow oil(0.4519 g, 1.02 mmol, 28%) and 0.4522 g of an impurity from the previousreaction. Unreduced acetamide (0.817 g, 1.68 mmol, 45%) is alsoobtained. This procedure is repeated on the acetamide to give (0.105 g,0.2 mmol, 6%) of unreacted starting material and additional free amine(0.245 g, 0.056 mmol, 14%): IR(film) 3360, 1380, 1325, 1260, 1160, 1125cm⁻¹ ; ¹ H NMR (CDCl₃) δ 1.23 (s, 6H), 1.64 (s, 3H), 1.71 (dt, J=6.8,13.8 Hz, 2H), 1.95 (br s, 3H), 2.11(q, J=7.3 , 14.5 Hz, 2H), 2.27(t,J=7.4,2H), 2.74 (t, 7.4 Hz, 2H), 3.81 (br s, 2H), 5.12 (t, J=7.2 Hz,1H), 5.4 (br s, 1H), 6.39 (br s, 1H), 6.56 (dd, J=2.5, 8.3 Hz, 1H), 6.66(br s, 1H), 7.32-7.39 (m, 4H)-(DMSO-d⁶) δ 1.13 (s, 6H), 1.55-1.60 (m,2H), 1.59 (s, 3H), 1.84 (s, 3H), 2.04 (dd, J=6.4, 14.5 Hz, 2H), 2.24 (t,J=7.9 Hz, 2H), 2.75 (t, J=7.6 Hz, 2H), 3.70 (t, J=6.3 Hz, 2H), 5.08 (t,J=6.4 Hz, 1H), 5.28 (s, 1H), 5.37 (s, 1H, exchanges with D₂₀), 6.36 (d,J=8.1 Hz, 1H), 6.47-6.50 (m, 2H), 7.47-7.51 (m, 4H); MS 443 m/e (M⁺).

Anal. Calcd. for C₂₇ H₃₂ NOF₃

C, 73.11; H, 7.27; N, 3.16.

Found: C, 73.15; H, 7.35; N, 3.14.

Other embodiments of the invention will be apparent to the skilled inthe art from a consideration of this specification or practice of theinvention disclosed herein. It is intended that the specification andexamples be considered as examplary only, with the true scope and spiritof the invention being indicated by the following claims.

We claim:
 1. A method of inhibiting cholesterol biosynthesis, loweringLDL cholesterol, and inhibiting LDL oxidation which comprisesadministering to a host in need thereof an effective amount of acompound having the formula ##STR13## wherein X is O, S or Ch₂ R¹ is Hor ##STR14## R² and R³ are independently H, C₁ -C₅ alkyl, CF₃, CN,halogen or OCH₃,n is an integer of 1 to 3, and m is an integer of 1 to3, or a pharmaceutically acceptable salt thereof.
 2. A method oftreating hypercholesterolemia, hyperlipidemia and atherosclerosis whichcomprises administering to a host in need thereof an effective amount ofa compound having the formula ##STR15## wherein X is O, S or Ch₂ R¹ is Hor ##STR16## R² and R³ are independently H, C₁ -C₅ alkyl, CF₃, CN,halogen or OCH₃,n is an integer of 1 to 3, and m is an integer of 1 to3, or a pharmaceutically acceptable salt thereof.